This is a competing renewal application by the Appalachian Tri-State (ATS) Node of NIDA's Clinical Trials Network (CTN) in response to RFA-DA-10-009. During the previous funding period, the ATS Node made substantial contributions to CTN research, dissemination and administrative activities. We collaborated effectively with NIDA, other Nodes and community treatment providers (CTPs) in advancing the mission of the CTN by: 1) participating in four clinical trials and preparing for a fifth; 2) contributing to new protocols under review; 3) writing a treatment manual for a trial; 4) developing and delivering clinical training protocols and fidelity scales for experimental interventions; 5) disseminating information about NIDA Evidenced-Based Treatments (EBTs) through lectures, training programs, conferences, writings for professionals and writings for patients with drug problems; and 6) participating in CTN committees, work groups and national and regional dissemination conference planning committees. Four new CTN trials were implemented during the past 4 years and ATS was one of three CTN Nodes that participated in all four, having excellent subject recruitment for three of four CTN studies by exceeding our original recruitment goals by randomizing 255 subjects in these trials. In response to the changing research needs of NIDA to conduct clinical trials in non-addiction treatment settings, the ATS node expanded our CTPs to include medical and psychiatric systems and an HIV primary care clinic. To demonstrate our ability to contribute conceptually to future CTN projects, we propose a research agenda that focuses on studies of substance use disorders (SUDs) that co-occur with psychiatric and/or medical conditions. Studies of co-occurring medical and mental health conditions are needed because of the high prevalence of SUDs among those who have other illnesses and the lack of studies for many specialized clinical populations, especially patients in medical settings. Potential CTN studies could focus on screening, identifying and engaging patients with SUDs in these non-addiction settings as well as examining dissemination and cost-effectiveness of the interventions.